Prognostic Impact of the Combined Effect of Lipoprotein(a) and Homocysteine in Patients with Premature Myocardial Infarction: a Prospective Cohort Study

Abstract Introduction Our previous study found that premature myocardial infarction (PMI) is frequently accompanied by multiple metabolic disorders. Lipoprotein(a) Lp(a) has been established as a predictor of major adverse cardiovascular events (MACE) in acute myocardial infarction 1. Homocysteine (HCY) is a new independent risk factor for cardiovascular disease that has been shown to be associated with the severity of coronary artery lesions 2. However, the combined effect of Lp(a) and HCY on long-term MACE in individuals with PMI remains unexplored. Purpose To investigate the combined prognostic effect of Lp(a) and HCY on MACE in PMI patients. Methods This prospective cohort study consecutively enrolled 1741 PMI patients (≤55 years) from xxx Hospital. Restricted cubic spline (RCS) analysis was employed to evaluate associations between Lp(a)/ HCY and MACE, with optimal cutoff values determined by integrating clinical reference thresholds. Lp(a) and HCY were dichotomized into binary variables (high/low levels), and patients were categorized into four groups through variable combination: low Lp(a)+low HCY, low Lp(a)+high HCY, high Lp(a)+low HCY, and high Lp(a)+high HCY. Kaplan-Meier (K-M) curves were generated to compare MACE-free survival across groups, while Cox proportional hazards regression models assessed the combined effect of Lp(a) and HCY on MACE risk. Stratified analyses were conducted to evaluate interactions in the overall population and subgroups with comorbid hypertension or diabetes. Results During a mean follow-up of 25.6 months, 224 patients (12.9%) experienced MACE. RCS analysis revealed a nonlinear association between Lp(a) and MACE in the overall population (P=0.002) and diabetes subgroup (P=0.049), but not in the hypertension subgroup (P=0.163). No nonlinear relationships were observed between HCY and MACE across all cohorts. In the overall population, elevated Lp(a) (50 mg/dL) (HR 2.383, 95% CI 1.778–3.193, P＜0.001) or HCY (15 μmol/L) (HR 1.964, 95% CI 1.486–2.596, P＜0.001) independently predicted increased MACE risk. Compared to the low Lp(a) and HCY reference group, patients with combined high Lp(a) and HCY exhibited the highest MACE risk: overall (HR 4.162, 95% CI 2.851–6.077, P0.001), hypertension subgroup (HR 4.140, 95% CI 2.487–6.892, P0.001), and diabetes subgroup (HR 4.277, 95% CI 2.112–8.658, P0.001). Significant interaction between Lp(a) and HCY was observed in the overall (P=0.003) and hypertension subgroup (P=0.046). Conclusion High HCY level is an independent predictor of MACE in PMI population. Meanwhile, the combined elevation of Lp (a) and HCY significantly increases the risk of MACE in PMI population, and it is necessary to jointly manage Lp (a) and HCY in hypertension and diabetes population.